RNAi-related inhibition of TNF alpha signaling pathway for treatment of ocular angiogenesis
View Patent ↗RNA interference is provided for inhibition of tumor necrosis factor α (TNFα) by silencing TNFα cell surface receptor TNF receptor-1 (TNFR1) mRNA expression, or by silencing TNFα converting enzyme (TACE/ADAM17) mRNA expression. Silencing such TNFα targets, in particular, is useful for treating patients having a TNFα-related condition or at risk of developing a TNFα-related condition, such as ocular angiogenesis, retinal ischemia, and diabetic retinopathy.
1. A double-stranded interfering RNA molecule having a length of about 19 to about 49 nucleotides, the interfering RNA molecule comprising:
(a) a sense strand having a region of at least 19 contiguous nucleotides corresponding to SEQ ID NO:21, except that the T's can be T's or U's; or
(b) an antisense strand having a region of at least 19 contiguous nucleotides complementary to SEQ ID NO:21.
2. The interfering RNA molecule of claim 1 wherein the sense strand and/or the antis-sense strand contains one or more chemically modified nucleotides.
3. The interfering RNA molecule of claim 1 , wherein the interfering RNA molecule has at least one blunt end.
4. The interfering RNA molecule of claim 1 , wherein the interfering RNA molecule comprises a 3′ overhang.
5. The interfering RNA molecule of claim 4 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides.
6. The interfering RNA molecule of claim 5 , wherein the 3′ overhang comprises 2 nucleotides.
7. The interfering RNA molecule of claim 2 , wherein the modified nucleotide comprises a ribose 2′-OH modification.
8. The interfering RNA molecule of claim 7 , wherein the ribose 2′-OH modification is selected from the group consisting of: 2′ amino group, 2′ O-methyl group, 2′ methoxyethyl group, and 2′-O,4′-C methylene bridge.
9. The interfering RNA molecule of claim 1 , wherein a phosphate group of the nucleotide is modified by substituting one or more of the oxygens of the phosphate group with nitrogen or with sulfur.
10. The interfering RNA molecule of claim 1 , wherein each strand of the double-stranded interfering RNA molecule is independently about 19 nucleotides to about 25 nucleotides in length.
11. The interfering RNA molecule of claim 10 , wherein each strand of the double-stranded interfering RNA molecule is independently about 19 nucleotides to about 23 nucleotides in length.
12. The interfering RNA molecule of claim 1 , wherein the interfering RNA molecule comprises a shRNA, a siRNA, or a miRNA.
13. A method of treating a TNFα-related ocular disorder in a patient in need thereof, comprising administering to the patient an interfering RNA molecule of claim 1 that attenuates expression of TACE mRNA via RNA interference, wherein the TNFα-related ocular disorder is ocular angiogenesis, ocular neovascularization, proliferative diabetic retinopathy, sequela associated with retinal ischemia, or posterior segment neovascularization (PSNV).
14. The method of claim 13 , wherein the sense and antisense strands are connected by a linker to form a shRNA that can attenuate expression of TACE mRNA in a patient.
15. The method of claim 13 , wherein the interfering RNA molecule is administered via in vivo expression from an expression vector capable of expressing the interfering RNA molecule.
16. The method of claim 13 , wherein the patient has or is at risk of developing a TNFα-related ocular disorder.
17. The method of claim 13 , wherein the interfering RNA molecule is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.